Human polymorphonuclear neutrophilic leukocytes (PMNs) contain large amounts of neutral proteases that can degrade elastin, collagen, proteoglycan, and basement membrane. The instillation of one of the purified enzymes (elastase) into dog lungs in vivo causes degradation of elastic fibers and other alveolar septal components and results in anatomic changes similar to those of human pulmonary emphysema. Cigarette smoking is a major risk factor associated with pulmonary emphysema in man. One mechanism for this association may be interference by smoke, with the regulation of PMN elastase activity by alveolar antiproteases. This possibility is supported by the observation that the oxidizing activity of tobacco smoke inactivates alpha1-proteinase inhibitor in vitro. Studies will next be conducted to evaluate the effects of inhaled cigarette smoke on the activity of lung alpha1-proteinase inhibitor in vivo. Parallel experiments will be carried out on the effects of smoke on another endogenous lung antiprotease (acid-stable bronchial mucous inhibitor). Macrophages also secrete an elastolytic protease, albeit at low levels. The short-term exposure of cultured mouse macrophages to cigarette smoke augments the rate of elastase secretion by these cells. Mouse macrophage elastase is not inhibited by alpha1-proteinase inhibitor or alpha2-macroglobulin. this unusual property of macrophage elastase may facilitate its attack upon elastin over prolonged intervals despite very low levels of macrophage elastase production. Studies on the characterization of the macrophage enzyme will be extended. Hopefully, a unified hypothesis of lung injury in pulmonary emphysema can be constructed involving both PMN and macrophage elastases and the actions of cigarette smoke.